1. Field of the Invention
The present invention relates to a composition for the prevention and treatment of autoimmune diseases comprising a double antagonist to TNF-α and TWEAK as an active ingredient.
2. Description of the Related Art
Immune system plays a role in protecting human body from antigens, the harmful foreign materials. Such antigens are exemplified by bacteria, viruses, toxic materials, cancer cells, and blood or tissues of other people or animals. Immune system produces antibodies to destroy such harmful foreign materials introduced. However, if immune system is mal-functioning, the system cannot distinguish normal health organs of its own from harmful foreign antigens, and thus it destroys normal tissues as well. This reaction is called autoimmune disease. Such reaction shows allergic hypersensitivity reaction. Allergy is the reaction against foreign materials that are not harmful for human body, but in the case of autoimmune disease, reaction target includes normal tissues. The reason why immune system cannot distinguish normal organs from antigens is not known. There is only assumed theory that microorganisms such as bacteria or drugs might cause such disease in those who are inherited specifically with such genes that are vulnerable to autoimmune disease.
Autoimmune disease is exemplified by Hashimoto's thyroiditis, pernicious anemia, Addison's disease, type 1 diabetes, autoimmune rheumatoid arthritis, Systemic lupus erythematosus, dermatomyositis, Sjogren syndrome, Lupus erythematosus, Multiple sclerosis, Myasthenia gravis, Reactive arthritis, Grave's disease, and Celiac disease—sprue, etc.
The purpose of the treatment of autoimmune disease is to regulate autoimmune response and to recover damaged immune function. The treatment method can be varied from the type of autoimmune disease. For example, if there is a problem in blood, blood transfusion is required. If any abnormality is observed in bone, joint, or muscle, physical exercise or other functional treatment is required. In addition, drug is prescribed in order to regulate immune response. Such drug is called immunosuppressive medicine, which is exemplified by corticosteroids such as prednisone and nonsteroids such as cyclophosphamide, azathioprine, and tacrolimus, etc.
Even though 21 million people world-widely, which are approximately 1% of the total population on earth, catch rheumatoid arthritis (RA), one of autoimmune disease, the reason of this disease has not been disclosed, yet. The symptom of rheumatoid arthritis is symmetric systemic chronic inflammation in diarthrodial joint. When it gets worse, even joint dysfunction occurs. Make matter worse, such mal-functioning of autoimmune system brings inflammation and pain not only in joint but also in other tissues around joint and further in other organs of entire body including lung, skin, and eye with causing pain and osteoporosis, resulting in severe decrease of life-quality making normal daily life impossible.
The previous treatment of rheumatoid arthritis focused on delaying the development of the disease or alleviating the accompanied pain by the improvement of life habit, surgical operation, and administration of a therapeutic agent, with inhibiting infection but without expecting any improvement of joint functions. However, the recent treatment is aiming at the full recovery of joint function. This has been made possible by the development of anti-TNF antagonists, which has been regarded the most dramatic discovery for the treatment of rheumatoid arthritis.
Tumor necrosis factor (TNF) is the pleiotropic cytokine, which plays an important role not only in inflammatory reaction but also in immune system. It is found in the joint of rheumatoid arthritis patient and colon of Crohn's disease patient. It has also been reported that tumor necrosis factor plays an important role in bone destruction, too. Therefore, all the treatment agents have been developed in order to inhibit TNF activity, precisely to interrupt signal transduction by binding to ligand belonging to TNF superfamily or to interrupt the bond between TNF ligand and receptor. To inhibit TNF signal transduction, monoclonal antibody against TNF ligand or recombinant protein has been used. Precisely, the treatment method using monoclonal antibody such as infliximab (Remicade) or adalimumab (Humira) has been used. And the treatment method using recombinant protein such as CTLA-41 g or entracept (Enbrel) has been also used. More precisely, infliximab is a chimera antibody comprising murine variable region and human IgG1 and κ constant region, which neutralizes the biological activity of TNF by binding to soluble, transmembrane TNF to inhibit the conjugation between TNF and its receptor. The structure of infliximab is similar to that of the natural antibody. Entracept is a fusion protein composed of extracellular domain of p75 TNF receptor and human IgG1 hinge and Fc domain. Infliximab, entracept, and adalimumab are the biological agents first accredited as rheumatoid arthritis treatment agents, which have been used for the past 10 years showing high efficiency. In addition to TNF, other cytokines have been targeted to develop a treatment agent. As DMARD (disease-modifying anti-rheumatic drugs) inhibiting interleukin, treatment agents have been developed targeting IL-6 or IL-1. However, the treatment effect is not as good as those of the anti-TNF agents.
TWEAK (TNF-related weak inducer of apoptosis) is an apoptosis inducer, which is a kind of ligands belonging to TNF superfamily. TWEAK is a cytokine that regulates a variety of cellular responses including anti-inflammatory response, angiogenesis, and cell division, etc. It was confirmed that inflammation in joint, angiogenesis in synovial membrane, and erosion of joint and bone were reduced, when TWEAK antibody was treated in CIA (collagen-induced arthritis) animal model before the development of the disease in order to inhibit TWEAK signal transduction (J. Immunol. 2006 Aug. 15; 177(4): 2610-20).
Despite the excellent treatment effect, the anti-TNF agents have many problems to overcome. One example is the side effect of the administration of anti-TNF agents, which is that TNF mechanism is stopped working, leading to mal-functioning of immune system with increasing risk of fungal or viral infection. Particularly, the chance of recurrence of dormant tuberculosis increases. In addition, demyelinating disorder such as multiple sclerosis or hematologic malignancies might be caused. According to rheumatoid society, chances of skin cancer development are higher in rheumatoid arthritis patients administered with anti-TNF agents than in those treated with the conventional therapeutic agents.
The treatment effect of the agent is not all the same among rheumatoid arthritis patients. Two thirds of the patients showed treatment effect, but one third of the patients were not improved. This result indicates that the treatment is limited by the medical history or genetic factors. Not only the pain from the disease but also the side effects accompanied by the treatment and the safety problems have to be considered and overcome. In the case of pregnant women having rheumatoid arthritis, the safety of fetus has been an issue when anti-TNF agent is administered. Scientists are faced with the task of developing diagnostic method to predict the treatment effect and the side effects thereby.
The present inventors tried to develop a novel therapeutic agent for autoimmune disease which is advantageous in overcoming the limitation of efficiency and safety matter of the conventional single antagonist used as an anti-TNF treatment agent. As a result, the inventors constructed TNFR2-TWEAKR fusion protein having antagonism against TNF-alpha (α) and TWEAK. The inventors further confirmed that when TNFR2-TWEAKR was treated to Th17 cells, the secretion of IL-17, the inflammatory cytokine, and the expression of RORc were all reduced, suggesting that TNFR2-TWEAKR had inhibitory effect on the secretion of inflammatory cytokine. At the same time, the inventors also confirmed that TNFR2-TWEAKR treatment resulted in up-regulation of IL-10, the anti-inflammatory cytokine secreted in autoimmune protective cells. In addition, RANKL, known to be involved in osteoclast, was also up-regulated in consistent with up-regulation of TWEAK in the serum of autoimmune arthritis patient. In CIA mouse model, the TNFR2-TWEAKR fusion protein of the present invention was confirmed to have not only the treatment effect on arthritis but also the treatment effect on autoimmune arthritis by increasing the expression of Tregs, the immune suppressive cells. Thus, the present inventors completed this invention by confirming the possibility of the TNFR2-TWEAKR fusion protein of the present invention as a novel treatment agent for autoimmune disease.